rs555848272

Variant names:

• chr5-141584111-TC-T
• rs555848272
• NM_005219.5:c.402+12delG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005219.5(DIAPH1):​c.402+12delG variant causes a intron change. The variant allele was found at a frequency of 0.00482 in 1,554,796 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (35 hom.)
• Consequence: DIAPH1 NM_005219.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.59
• Publications: 1 publications found

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DIAPH1 Gene-Disease associations (from GenCC):

• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 5-141584111-TC-T is Benign according to our data. Variant chr5-141584111-TC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163077.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00377 (574/152188) while in subpopulation AMR AF = 0.0109 (167/15278). AF 95% confidence interval is 0.00958. There are 5 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	NM_005219.5	MANE Select	c.402+12delG		intron	N/A	NP_005210.3
	DIAPH1	NM_001079812.3		c.375+12delG		intron	N/A	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.402+12delG		intron	N/A	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.402+12delG		intron	N/A	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.375+12delG		intron	N/A	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.402+12delG		intron	N/A	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152076 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00375 AC: 929 AN: 247676 AF XY: 0.00364

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.00757

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00529

Gnomad OTH exome AF: 0.00532

GnomAD4 exome AF: 0.00494 AC: 6923 AN: 1402608 Hom.: 35 Cov.: 25 AF XY: 0.00481 AC XY: 3371 AN XY: 700776

African (AFR) AF: 0.00105 AC: 34 AN: 32240

American (AMR) AF: 0.00828 AC: 369 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.000233 AC: 6 AN: 25784

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39420

South Asian (SAS) AF: 0.000472 AC: 40 AN: 84800

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53344

Middle Eastern (MID) AF: 0.00246 AC: 14 AN: 5684

European-Non Finnish (NFE) AF: 0.00584 AC: 6180 AN: 1058332

Other (OTH) AF: 0.00447 AC: 261 AN: 58438

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152188 Hom.: 5 Cov.: 32 AF XY: 0.00372 AC XY: 277 AN XY: 74418

African (AFR) AF: 0.000963 AC: 40 AN: 41522

American (AMR) AF: 0.0109 AC: 167 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00513 AC: 349 AN: 68000

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00404 Hom.: 1

Bravo AF: 0.00438

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (1)
-	1	-	Nonsyndromic Hearing Loss, Mixed (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs555848272; hg19: chr5-140963678;